title: Toll-like receptor 4 inhibitor TAK-242 attenuates acute kidney injury in endotoxemic sheep.
abstract: BACKGROUND
  This study was conducted to investigate the role of toll-like receptor 4 (TLR4) in mediating acute kidney injury in endotoxemic sheep using the selective TLR4 inhibitor TAK-242.
  
  
  METHODS
  A randomized, controlled, experimental study was performed with 20 adult Texel crossbred sheep. Before an Escherichia coli lipopolysaccharide infusion (3 μg · kg(-1) · h(-1) for 24 h), sheep were randomized to receive a bolus dose (2 mg/kg), followed by a continuous infusion (4 mg · kg(-1) · 24 h(-1)) of either TAK-242 (n = 7) or vehicle (n = 7). A third group of lipopolysaccharide-treated sheep (n = 6) received norepinephrine, titrated to maintain baseline arterial blood pressure.
  
  
  RESULTS
  Endotoxin infusion established a state of hyperdynamic circulation, with an increased cardiac index, hypotension, and tachycardia. Urine output and creatinine clearance decreased throughout the experiment, together with increasing plasma creatinine, blood urea nitrogen, and arterial lactate concentrations. After 24 h, TLR4 inhibition had significantly (P ≤ 0.001) attenuated the mean ± SEM decrease in arterial pressure (97 ± 3 vs. 71 ± 4 mmHg), urine output (1.16 ± 0.15 vs. 0.13 ± 0.05 ml · kg(-1) · h(-1)), and creatinine clearance (126 ± 13 vs. 20 ± 7 ml/min) compared with vehicle-treated animals. Furthermore, arterial lactate, plasma creatinine, and blood urea nitrogen concentrations were significantly lower in the TAK-242 group versus the vehicle-treated animals. Compared with TLR4 inhibition, norepinephrine caused similar effects on arterial pressure, cardiac index, and heart rate; however, it did not attenuate the decrease in urine output or creatinine clearance.
  
  
  CONCLUSIONS
  These results indicate a critical role for TLR4 in impairing renal function during ovine endotoxemia that is independent of changes in central hemodynamics.
authors.affiliation: Department of Anaesthesia and Intensive Care, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Fenhammar
authors.forename: Mats
authors.initials: M
authors.lastname: Rundgren
authors.forename: Jakob
authors.initials: J
authors.lastname: Forestier
authors.forename: Sigridur
authors.initials: S
authors.lastname: Kalman
authors.forename: Stefan
authors.initials: S
authors.lastname: Eriksson
authors.forename: Robert
authors.initials: R
authors.lastname: Frithiof
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D001806:Blood Urea Nitrogen; D002302:Cardiac Output / Q000187:drug effects; D003404:Creatinine / Q000097:blood / Q000652:urine; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000150:complications*; D005260:Female; D007022:Hypotension / Q000209:etiology / Q000378:metabolism; D019344:Lactic Acid / Q000097:blood; D008070:Lipopolysaccharides; D009638:Norepinephrine / Q000008:administration & dosage; D012756:Sheep; D013449:Sulfonamides / Q000378:metabolism* / Q000494:pharmacology; D013610:Tachycardia / Q000209:etiology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D013449:Sulfonamides; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D019344:Lactic Acid; D003404:Creatinine; D009638:Norepinephrine